The compounds of the present invention are antagonists of the VLA-4 integrin (xe2x80x9cvery late antigen-4xe2x80x9d; CD49d/CD29; or xcex14xcex21) and/or the xcex14xcex27 integrin (LPAM-1 and xcex14xcex2p), thereby blocking the binding of VLA-4 to its various ligands, such as VCAM-1 and regions of fibronectin, and xcex14xcex27 to its various ligands, such as MadCAM-1, VCAM-1 and fibronectin. Thus, these antagonists are useful in inhibiting cell adhesion processes including cell activation, migration, proliferation and differentiation. These antagonists are useful in the treatment, prevention and suppression of diseases mediated by VLA-4- and/or xcex14xcex27-binding and cell adhesion and activation, such as AIDS-related dementia, allergic conjunctivitis, allergic rhinitis, Alzheimer""s disease, aortic stenosis, asthma, atherosclerosis, autologous bone marrow transplantation, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, inflammatory bowel disease including ulcerative colitis and Crohn""s disease, inflammatory lung diseases, inflammatory sequelae of viral infections, meningitis, multiple sclerosis, myocarditis, organ transplantation, psoriasis, restenosis, retinitis, rheumatoid arthritis, septic arthritis, stroke, tumor metastasis, type I diabetes, and vascular occlusion following angioplasty.
The present invention relates to susbstituted cyclic amine derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesion-mediated pathologies. This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
Many physiological processes require that cells come into close contact with other cells and/or extracellular matrix. Such adhesion events may be required for cell activation, migration, proliferation and differentiation. Cell-cell and cell-matrix interactions are mediated through several families of cell adhesion molecules (CAMs) including the selectins, integrins, cadherins and immunoglobulins. CAMs play an essential role in both normal and pathophysiological processes. Therefore, the targetting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell-cell and cell-matrix interactions.
The integrin superfamily is made up of structurally and functionally related glycoproteins consisting of xcex1 and xcex2 heterodimeric, transmembrane receptor molecules found in various combinations on nearly every mammalian cell type. (for reviews see: E. C. Butcher, Cell, 67, 1033 (1991); T. A. Springer, Cell, 76, 301 (1994); D. Cox et al., xe2x80x9cThe Pharmacology of the Integrins.xe2x80x9d Medicinal Research Rev. 14, 195 (1994) and V. W. Engleman et al., xe2x80x9cCell Adhesion Integrins as Pharmaceutical Targets.xe2x80x9d in Ann. Repts. in Medicinal Chemistry, Vol. 31, J. A. Bristol, Ed.; Acad. Press, N.Y., 1996, p. 191).
VLA-4 (xe2x80x9cvery late antigen-4xe2x80x9d; CD49d/CD29; or xcex14xcex21) is an integrin expressed on all leukocytes, except platelets and mature neutrophils, including dendritic cells and macrophage-like cells and is a key mediator of the cell-cell and cell-matrix interactions of these cell types (see M. E. Hemler, xe2x80x9cVLA Proteins in the Integrin Family: Structures, Functions, and Their Role on Leukocytes.xe2x80x9d Ann. Rev. Immunol. 8, 365 (1990)). The ligands for VLA-4 include vascular cell adhesion molecule-1 (VCAM-1) and the CS-1 domain of fibronectin (FN). VCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells at sites of inflammation. (See R. Lobb et al. xe2x80x9cVascular Cell Adhesion Molecule 1.xe2x80x9d in Cellular and Molecular Mechanisms of Inflammation, C. G. Cochrane and M. A. Gimbrone, Eds.; Acad. Press, San Diego, 1993, p. 151.) VCAM-1 is produced by vascular endothelial cells in response to pro-inflammatory cytokines (See A. J. H. Gearing and W. Newman, xe2x80x9cCirculating adhesion molecules in disease.xe2x80x9d, Immunol. Today, 14, 506 (1993). The CS-1 domain is a 25 amino acid sequence that arises by alternative splicing within a region of fibronectin. (For a review, see R. O. Hynes xe2x80x9cFibronectins.xe2x80x9d, Springer-Velag, N.Y., 1990.) A role for VLA-4/CS-1 interactions in inflammatory conditions has been proposed (see M. J. Elices, xe2x80x9cThe integrin xcex14xcex21 (VLA-4) as a therapeutic targetxe2x80x9d in Cell Adhesion and Human Disease, Ciba Found. Symp., John Wiley and Sons, N.Y., 1995, p. 79).
xcex14xcex27 (also referred to as LPAM-1 and xcex14xcex2p) is an integrin expressed on leukocytes and is a key mediator of leukocyte trafficking and homing in the gastrointestinal tract (see C. M. Parker et al., Proc. Natl. Acad. Sci. USA, 89, 1924 (1992)). The ligands for xcex14xcex27 include mucosal addressing cell adhesion molecule-1 (MadCAM-1) and, upon activation of xcex14xcex27, VCAM-1 and fibronectin (Fn). MadCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells of gut-associated mucosal tissues of the small and large intestine (xe2x80x9cPeyer""s Patchesxe2x80x9d) and lactating mammary glands. (See M. J. Briskin et al., Nature, 363, 461 (1993); A. Hamann et al., J. Immunol., 152, 3282 (1994)). MadCAM-1 can be induced in vitro by proinflammatory stimuli (See E. E. Sikorski et al. J. Immunol., 151, 5239 (1993)). MadCAM-1 is selectively expressed at sites of lymphocyte extravasation and specifically binds to the integrin, xcex14xcex27.
Neutralizing anti-xcex14 antibodies or blocking peptides that inhibit the interaction between VLA-4 and/or xcex14xcex27 and their ligands have proven efficacious both prophylactically and therapeutically in several animal models of disease, including i) experimental allergic encephalomyelitis, a model of neuronal demyelination resembling multiple sclerosis (for example, see T. Yednock et al., xe2x80x9cPrevention of experimental autoimmune encephalomyelitis by antibodies against xcex14xcex21 integrin.xe2x80x9d Nature, 356, 63 (1993) and E. Keszthelyi et al., xe2x80x9cEvidence for a prolonged role of xcex14 integrin throughout active experimental allergic encephalomyelitis.xe2x80x9d Neurology, 47, 1053 (1996)); ii) bronchial hyperresponsiveness in sheep and guinea pigs as models for the various phases of asthma (for example, see W. M. Abraham et al., xe2x80x9cxcex14-Integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.xe2x80x9d J. Clin. Invest. 93, 776 (1993) and A. A. Y. Milne and P. P. Piper, xe2x80x9cRole of VLA-4 integrin in leucocyte recruitment and bronchial hyperresponsiveness in the gunea-pig.xe2x80x9d Eur. J. Pharmacol., 282, 243 (1995)); iii) adjuvant-induced arthritis in rats as a model of inflammatory arthritis (see C. Barbadillo et al., xe2x80x9cAnti-VLA-4 mAb prevents adjuvant arthritis in Lewis rats.xe2x80x9d Arthr. Rheuma. (Suppl.), 36 95 (1993) and D. Seiffge, xe2x80x9cProtective effects of monoclonal antibody to VLA-4 on leukocyte adhesion and course of disease in adjuvant arthritis in rats.xe2x80x9d J. Rheumatol., 23, 12 (1996)); iv) adoptive autoimmune diabetes in the NOD mouse (see J. L. Baron et al., xe2x80x9cThe pathogenesis of adoptive murine autoimmune diabetes requires an interaction between xcex14-integrins and vascular cell adhesion molecule-1.xe2x80x9d, J. Clin. Invest., 93, 1700 (1994), A. Jakubowski et al., xe2x80x9cVascular cell adhesion molecule-Ig fusion protein selectively targets activated xcex14-integrin receptors in vivo: Inhibition of autoimmune diabetes in an adoptive transfer model in nonobese diabetic mice.xe2x80x9d J. Immunol., 155, 938 (1995), and X. D. Yang et al., xe2x80x9cInvolvement of beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MadCAM-1) in the development of diabetes in nonobese diabetic micexe2x80x9d, Diabetes, 46, 1542 (1997)); v) cardiac allograft survival in mice as a model of organ transplantation (see M. Isobe et al., xe2x80x9cEffect of anti-VCAM-1 and anti-VLA-4 monoclonal antibodies on cardiac allograft survival and response to soluble antigens in mice.xe2x80x9d, Tranplant. Proc., 26, 867 (1994) and S. Molossi et al., xe2x80x9cBlockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteripathy in rabbit cardiac allografts.xe2x80x9d J. Clin Invest., 95, 2601 (1995)); vi) spontaneous chronic colitis in cotton-top tamarins which resembles human ulcerative colitis, a form of inflammatory bowel disease (see D. K. Podolsky et al., xe2x80x9cAttenuation of colitis in the Cotton-top tamarin by anti-xcex14 integrin monoclonal antibody.xe2x80x9d, J. Clin. Invest., 92, 372 (1993)); vii) contact hypersensitivity models as a model for skin allergic reactions (see T. A. Ferguson and T. S. Kupper, xe2x80x9cAntigen-independent processes in antigen-specific immunity.xe2x80x9d, J. Immunol., 150, 1172 (1993) and P. L. Chisholm et al., xe2x80x9cMonoclonal antibodies to the integrin xcex1-4 subunit inhibit the murine contact hypersensitivity response.xe2x80x9d Eur. J. Immunol., 23, 682 (1993)); viii) acute neurotoxic nephritis (see M. S. Mulligan et al., xe2x80x9cRequirements for leukocyte adhesion molecules in nephrotoxic nephritis.xe2x80x9d, J. Clin. Invest., 91, 577 (1993)); ix) tumor metastasis (for examples, see M. Edward, xe2x80x9cIntegrins and other adhesion molecules involved in melanocytic tumor progression.xe2x80x9d, Curr. Opin. Oncol., 7, 185 (1995)); x) experimental autoimmune thyroiditis (see R. W. McMurray et al., xe2x80x9cThe role of xcex14 integrin and intercellular adhesion molecule-1 (ICAM-1) in murine experimental autoimmune thyroiditis.xe2x80x9d Autoimmunity, 23, 9 (1996); and xi) ischemic tissue damage following arterial occlusion in rats (see F. Squadrito et al., xe2x80x9cLeukocyte integrin very late antigen-4/vascular cell adhesion molecule-1 adhesion pathway in splanchnic artery occlusion shock.xe2x80x9d Eur. J. Pharmacol., 318, 153 (1996); xii) inhibition of TH2 T-cell cytokine production including IL-4 and IL-5 by VLA-4 antibodies which would attenuate allergic responses (J.Clinical Investigation 100, 3083 (1997). The primary mechanism of action of such antibodies appears to be the inhibition of lymphocyte and monocyte interactions with CAMs associated with components of the extracellular matrix, thereby limiting leukocyte migration to extravascular sites of injury or inflammation and/or limiting the priming and/or activation of leukocytes.
There is additional evidence supporting a possible role for VLA-4 interactions in other diseases, including rheumatoid arthritis; various melanomas, carcinomas, and sarcomas, including multiple myeloma; inflammatory lung disorders; acute respiratory distress syndrome (ARDS); pulmonary fibrosis; atherosclerotic plaque formation; restenosis; uveitis; and circulatory shock (for examples, see A. A. Postigo et al., xe2x80x9cThe xcex14xcex21/VCAM-1 adhesion pathway in physiology and disease.xe2x80x9d, Res. Immunol., 144, 723 (1994) and J.-X. Gao and A. C. Issekutz, xe2x80x9cExpression of VCAM-1 and VLA-4 dependent T-lymphocyte adhesion to dermal fibroblasts stimulated with proinflammatory cytokines.xe2x80x9d Immunol. 89, 375 (1996)).
At present, there is a humanized monoclonal antibody (Antegren(copyright), Athena Neurosciences/Elan ) against VLA-4 in clinical development for the treatment of multiple sclerosis and Crohn""s disease and a humanized monoclonal antibody (ACT-1/(copyright)/LDP-02 Millenium/Genentech) against xcex14xcex27 in clinical development for the treatment of inflammatory bowel disease. Several classes of antagonists of VLA-4 and xcex14xcex27 have been described: (D. Y. Jackson et al., xe2x80x9cPotent xcex14xcex21 peptide antagonists as potential anti-inflammatory agentsxe2x80x9d, J. Med. Chem., 40, 3359 (1997); H. N. Shroff et al., xe2x80x9cSmall peptide inhibitors of xcex14xcex27 mediated MadCAM-1 adhesion to lymphocytesxe2x80x9d, Bioorg. Med. Chem. Lett., 6, 2495 (1996); A. J. Soures et al., Bioorg. Med. Chem. Lett., 8, 2297 (1998); K. C. Lin et al., xe2x80x9cSelective, tight-binding inhibitors of integrin xcex14xcex21 that inhibit allergic airway responsesxe2x80x9d, J. Med. Chem., 42, 920 (1999); S. P. Adams and R. R. Lobb, xe2x80x9cInhibitors of Integrin Alpha 4 Beta 1 (VLA-4).xe2x80x9d in Ann. Repts. in Medicinal Chemistry, Vol. 34, A. M. Doherty, Ed.; Acad. Press, N.Y., 1999, p. 179; L. Chen et al.,xe2x80x9cN-Acyl phenyhlalanine analogues as VCAM/VLA-4 antagonistsxe2x80x9d, Bioorg. Med. Chem. Lett., 10, 725 (2000); L. Chen et al.,xe2x80x9cN-Benzylpyroglutamate-L-phenyhlalanine derivatives as potent small molecule VLA-4 antagonistsxe2x80x9d, Bioorg. Med. Chem. Lett., 10, 729 (2000);U.S. Pat. No. 5,510,332, WO00/18759, WO00/18760, WO00/15612, WO00/05224, WO00/05223, WO00/01690, WO00/00477, WO99/67230, WO99/61465, WO99/54321, WO99/47547, WO99/43642, WO99/37618, WO99/37605, WO99/36393, WO99/35163, WO99/24398, WO99/23063, WO98/58902, WO98/54207, WO97/03094, WO97/02289, WO96/40781, WO96/40641, WO96/31206, WO96/22966, WO96/20216, WO96/06108, WO96/01644, WO95/15973, EP0918059A1, EP0842943A2, EP0905139A2, EP0903353A1,. There still remains a need for low molecular weight, specific inhibitors of VLA-4 and xcex14xcex27-dependent cell adhesion that have improved pharmacokinetic and pharmacodynamic properties such as oral bioavailability and significant duration of action. Such compounds would prove to be useful for the treatment, prevention or suppression of various pathologies mediated by VLA-4 and xcex14xcex27 binding and cell adhesion and activation.
The present invention provides novel compounds of formula I: 
or a pharmaceutically acceptable salt thereof wherein:
R1 is
1) hydrogen,
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
R2 is
1) C1-10alkyl,
2) Ar1,
3) Ar1xe2x80x94C1-10alkyl,
4) Ar1xe2x80x94Ar2,
5) Ar1xe2x80x94Ar2xe2x80x94C1-10alkyl-,
wherein the alkyl group is optionally substituted with one to four substituents selected from Ra, and Ar1 and Ar2 are optionally substituted with one to four substituents independently selected from Rb,
R3 is
1) hydrogen,
2) C1-10alkyl,
3) C2-10alkenyl,
4) C2-10alkynyl,
wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra;
R4 is
1) hydroxy,
2) C1-10alkoxy,
3) C2-10alkenyloxy,
4) C2-10alkynyloxy,
5) Cy-Oxe2x80x94,
6) Cy-C1-10alkoxy,
7) amino,
8) C1-10alkylamino,
9) di(C1-10alkyl)amino,
10) Cy-C1-10alkylamino,
wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and Cy is optionally substituted with one to four substituents independently selected from Rb;
R5, R6, and R7 are independently selected from
1) hydrogen,
2) C1-10 alkyl,
3) C2-10 alkenyl,
4) C2-10 alkynyl,
5) cycloalkyl,
6) heterocyclyl,
7) aryl;
8) aryl C1-10alkyl,
9) heteroaryl;
10) heteroaryl C1-10alkyl,
11) xe2x80x94ORd,
13) xe2x80x94NO2,
14) halogen
15) xe2x80x94S(O)mRd,
16) xe2x80x94SRd,
17) xe2x80x94S(O)2ORd,
8) xe2x80x94S(O)mNRdRe,
19) xe2x80x94NRdRe,
20) xe2x80x94O(CRfRg)nNRdRe,
21) xe2x80x94C(O)Rd,
22) xe2x80x94CO2Rd,
23) xe2x80x94CO2(CRfRg)nCONRdRe,
24) xe2x80x94OC(O)Rd,
25) xe2x80x94CN,
26) xe2x80x94C(O)NRdRe,
27) xe2x80x94NRdC(O)Re,
28) xe2x80x94OC(O)NRdRe,
29) xe2x80x94NRdC(O)ORe,
30) xe2x80x94NRdC(O)NRdRe,
31) xe2x80x94CRd(Nxe2x80x94ORe),
32) CF3; or
33) xe2x80x94OCF3;
wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one to four substituents selected from a group independently selected from Rb, with the proviso that when R5, R6, or R7 are attached to the ring by nitrogen, sulfur or oxygen, they may not be atached to the ring atom adjacent to A when A is other than carbon; or
R5 and R6 together with the atom or atoms to which they are attached form a fused or spirocyclic ring of 4 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
R8 is
1) hydrogen,
2) C1-10 alkyl,
3) C2-10 alkenyl,
4) C2-10 alkynyl,
5) aryl,
6) heteroaryl,
7) aryl C1-10alkyl,
8) heteroaryl C1-10 alkyl,
9) xe2x80x94ORd,
10) xe2x80x94O(CRfRg)nNRdRe,
11) xe2x80x94OC(O)Rd,
12) xe2x80x94OC(O)NRdRe,
13) halogen,
14) xe2x80x94SRd,
15) xe2x80x94S(O)mRd,
16) xe2x80x94S(O)2ORd,
17) xe2x80x94S(O)mNRdRe,
18) xe2x80x94NO2,
19) xe2x80x94NRdRe,
20) xe2x80x94NRdC(O)Re,
21) xe2x80x94NRdS(O)mRe,
22) xe2x80x94NRdC(O)ORe, or
23) xe2x80x94NRdC(O)NRdRe,
wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with one to four substituents selected from a group independently selected from Rc;
R9 is
1) hydrogen,
2) C1-10 alkyl,
3) C2-10 alkenyl,
4) C2-10 alkynyl,
5) cycloalkyl,
6) heterocyclyl,
7) aryl,
8) heteroaryl;
9) aryl C1-10alkyl,
10) heteroaryl C1-10 alkyl,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one to four substituents selected from a group independently selected from Rc;
Ra is
1) hydrogen,
2) xe2x80x94ORd,
3) xe2x80x94NO2,
4) halogen
5) xe2x80x94S(O)mRd,
6) xe2x80x94SRd,
7) xe2x80x94S(O)2ORd,
8) xe2x80x94S(O)mNRdRe,
9) xe2x80x94NRdRe,
10) xe2x80x94O(CRfRg)nNRdRe,
11) xe2x80x94C(O)Rd,
12) xe2x80x94CO2Rd,
13) xe2x80x94CO2(CRfRg)nCONRdRe,
14) xe2x80x94OC(O)Rd,
15) xe2x80x94CN,
16) xe2x80x94C(O)NRdRe,
17) xe2x80x94NRdC(O)Re,
18) xe2x80x94OC(O)NRdRe,
19) xe2x80x94NRdC(O)ORe,
20) xe2x80x94NRdC(O)NRdRe,
21) xe2x80x94CRd(Nxe2x80x94ORe),
22) CF3; or
23) xe2x80x94OCF3;
Rb is
1) a group selected from Ra,
2) C1-10 alkyl,
3) C2-10 alkenyl,
4) C2-10 alkynyl,
5) cycloalkyl,
6) heterocyclyl,
7) aryl;
8) aryl C1-10alkyl,
9) heteroaryl;
10) heteroaryl C1-10 alkyl,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one to four substituents selected from a group independently selected from Rc;
Rc is
1) halogen,
2) xe2x80x94NRdRe,
3) carboxy,
4) cyano,
5) C1-4alkyl,
6) C1-4alkoxy,
7) aryl,
8) aryl C1-4alkyl,
9) heteroaryl,
10) hydroxy,
11) xe2x80x94CF3,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one to four substituents selected from a group independently selected from Rc;
Rd and Re are independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, Cy and Cy C1-10alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or
Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rf and Rg are independently selected from hydrogen, C1-10alkyl, Cy and Cy-C1-10alkyl; or
Rf and Rg together with the carbon to which they are attached form a ring of 4 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
Rh is
1) hydrogen,
2) xe2x80x94ORd,
3) xe2x80x94NO2,
4) xe2x80x94S(O)mRd,
5) xe2x80x94S(O)2ORd,
6) xe2x80x94NRdRe,
7) xe2x80x94C(O)Rd,
8) xe2x80x94CO2Rd,
9) xe2x80x94CN,
10) xe2x80x94C(O)NRdRe,
11) C1-10 alkyl,
12) C2-10 alkenyl,
13) C2-10 alkynyl,
14) cycloalkyl,
15) heterocyclyl,
16) aryl;
17) aryl C1-10alkyl,
18) heteroaryl, or
19) heteroaryl C1-10 alkyl,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one to four substituents selected from a group independently selected from Rc;
Cy is independently selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;
Ar1 and Ar2 are independently selected from aryl and heteroaryl;
m is an integer from 1 to 2;
n is an integer from 1 to 10;
r is an integer from 0 to 4;
s is an integer from 1 to 5;
r+s is an integer from 2 to 5 when A is carbon, oxygen, Nxe2x80x94(Rh)xe2x80x94 or xe2x80x94S(O)m-;
r+s is an integer from 1 to 4 when A is xe2x80x94C(xe2x95x90O)N(Rh)xe2x80x94, xe2x80x94Oxe2x80x94N(Rh)xe2x80x94 or S(O)2N(Rh)xe2x80x94;
A is
1) carbon,
2) oxygen,
3) xe2x80x94N(Rh)xe2x80x94,
4) xe2x80x94C(xe2x95x90O)N(Rh)xe2x80x94,
5) xe2x80x94Oxe2x80x94N(Rh)xe2x80x94,
6) xe2x80x94S(O)2N(Rh)xe2x80x94,
7) xe2x80x94S(O)m;
Y is
1) a bond, or
2) xe2x80x94C(R8)(R9)-.
xe2x80x9cAlkylxe2x80x9d, as well as other groups having the prefix xe2x80x9calkxe2x80x9d, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
xe2x80x9cAlkenylxe2x80x9d means carbon chains which contain at least one carbonxe2x80x94carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d means carbon chains which contain at least one carbonxe2x80x94carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
xe2x80x9cCycloalkylxe2x80x9d means mono- or bicyclic saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms. The term also includes monocyclic rings fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
xe2x80x9cArylxe2x80x9d means mono- or bicyclic aromatic rings containing only carbon atoms. The term also includes aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
xe2x80x9cHeterocyclylxe2x80x9d means mono- or bicyclic saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. The term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of xe2x80x9cheterocyclylxe2x80x9d include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils).
xe2x80x9cHalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine.
Examples of the heterocycle 
include, but are not limited to, 
In another subset of compounds of formula I, Y is a bond, R3 is hydrogen, and R2 is Ar1xe2x80x94Ar2, Ar1xe2x80x94Ar2xe2x80x94C1-10alkyl, Ar1 or Ar1xe2x80x94C1-10alkyl wherein Ar1 and Ar2 are optionally substituted with one to four groups selected from Rb. Examples of suitable R2 within this subset are: 
wherein W, n, R5 and R6 are as defined in PCT Published Application WO 99/36393 (Tanabe); the relevant definitions as well as specific exemplification of such definitions are hereby incorporated by reference; 
wherein X and Xxe2x80x2 are as defined in WO99/10312 (Hoffmann-LaRoche); the relevant definitions as well as specific exemplification of such definitions are hereby incorporated by reference;
(3) xe2x80x94(CH2)xxe2x80x94Ar-R5xe2x80x2 wherein x, Ar, R5xe2x80x2 are as defined in Athena""s WO99/06431, WO99/06434, WO99/06390; the relevant definitions as well as specific exemplification of such definitions are hereby incorporated by reference.
(4) xe2x80x94(CH2)xe2x80x94X wherein X, to the extent it is within the scope of Ar1 and Ar1xe2x80x94Ar2, is as defined in Athena""s WO99/06437, WO99/06433, WO99/06435;
(5) xe2x80x94(CH2)n-aryl or xe2x80x94(CH2)n-heteroaryl, wherein n and aryl and heteroaryl are as defined in WO99/06436 (Athena); 
wherein Alk, m, R, R2, R3 are as defined in WO98/54207 (Celltech).
(7) Ar1xe2x80x94Ar2xe2x80x94C1-10alkyl wherein Ar1 and Ar2 are as defined in WO98/53817;
(8) Cy or Cy-C1-10alkyl, wherein Cy to the extent it is within the scope of Ar1, is as defined in WO98/53818.
In another subset of compounds of formula I, R7 is CO2H and pharmaceutically acceptable salt thereof.
Optical Isomersxe2x80x94Diastereomersxe2x80x94Geometric Isomersxe2x80x94Tautomers
Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
Alternatively, any enantiomer of a compound of the general Formula I or Ia may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Salts
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Utilities
The ability of the compounds of Formula I to antagonize the actions of VLA-4 and/or xcex14xcex27 integrin makes them useful for preventing or reversing the symptoms, disorders or diseases induced by the binding of VLA-4 and or xcex14xcex27to their various respective ligands. Thus, these antagonists will inhibit cell adhesion processes including cell activation, migration, proliferation and differentiation. Accordingly, another aspect of the present invention provides a method for the treatment (including prevention, alleviation, amelioration or suppression) of diseases or disorders or symptoms mediated by VLA-4 and/or xcex14xcex27 binding and cell adhesion and activation, which comprises administering to a mammal an effective amount of a compound of Formula I. Such diseases, disorders, conditions or symptoms are for example (1) multiple sclerosis, (2) asthma, (3) allergic rhinitis, (4) allergic conjunctivitis, (5) inflammatory lung diseases, (6) rheumatoid arthritis, (7) septic arthritis, (8) type I diabetes, (9) organ transplantation rejection, (10) restenosis, (11) autologous bone marrow transplantation, (12) inflammatory sequelae of viral infections, (13) myocarditis, (14) inflammatory bowel disease including ulcerative colitis and Crohn""s disease, (15) certain types of toxic and immune-based nephritis, (16) contact dermal hypersensitivity, (17) psoriasis, (18) tumor metastasis, and (19) atherosclerosis.
Dose Ranges
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
For use where a composition for intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
In the case where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 100 mg of a compound of Formula I per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 10 mg to about 100 mg) of a compound of Formula I per kg of body weight per day.
For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used.
Pharmaceutical Compositions
Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The term xe2x80x9ccompositionxe2x80x9d, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which may be formulated as a dry powder of a compound of Formula I with or without additional excipients.
Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:
Combination Therapy
Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) other VLA-4 antagonists such as those described in U.S. Pat. No. 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as xcex22-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, salmeterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) antagonists of the chemokine receptors, especially CCR-1, CCR-2, and CCR-3; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), a-glucosidase inhibitors (acarbose) and glitazones (troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like); (1) preparations of interferon beta (interferon beta-1a, interferon beta-1b); (m) anticholinergic agents such as muscarinic antagonists (ipratropium bromide); (n) other compounds such as 5-aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents.
The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID the weight ratio of the compound of the Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
Compounds of the present invention may be prepared by procedures illustrated in the accompanying Schemes. Appropriately protected amino acid derivatives may be synthesized as outlined in Scheme 1. N-(t-Butyloxycarbonyl) amino acid A is treated with t-butyl 2,2,2-trichloroacetimidate in the presence of a Lewis acid (boron trifluoride-etherate) to form protected amino acid ester B. Likewise, the free amino acid C is reacted with isobutylene in the presence of sulfuric acid to form t-butyl ester followed by reaction with BOC-ON to form B. 
Biaryl amino acid derivatives are prepared by application of Stille-type carbonxe2x80x94carbon bond forming conditions (A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc., 109, 5478 (1987); Farina et al., J. Org. Chem. 5434, (1993)). In Scheme 2, the aryl bromide or iodide intermediate A is converted into its trialkyltin derivative B using hexamethylditin (((CH3)3Sn)2) in the presence of a palladium(0) catalyst and lithium chloride and then reacted with an appropriately substituted aryl or heteroaryl bromide, iodide, or triflate in the presence of a palladium reagent, such as tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0), in a suitable solvent, such as toluene, dioxane, DMF, or 1-methyl-2-pyrrolidinone, followed by the removal of the tert-butyl ester using strong acid (TFA) to yield the desired product C. The BOC protecting group is subsequently removed treatment with strong acid (HCl, H2SO4, or TFA) to form D. 
Alternatively, a boronate ester derivative A is carefully hydrolyzed to the boronic acid B (Scheme 3). Substituted aryl- or heteroaryl-halides or -triflates are coupled to B in the presence of a palladium(0) reagent, such as tetrakis(triphenylphosphine)palladium under Suzuki conditions (N. Miyaura et al., Synth. Commun., 1981, 11, 513-519) to form C. Alternatively, alkene derivatives, acid chlorides or amides may be coupled to the boronic acid to form C. The BOC group may be selectively removed in the presence of sulfuric acid in t-butyl acetate to yield amino acid ester D. 
Lactams A are treated with Lawesson""s reagent to form thiolactam B (Scheme 4). Alkylation with methyliodide or dimethylsulfate produces isothiouronium salt C. Amino acid ester D is reacted with C to form amidine derivative E. Treatment of ester E with strong acid (TFA or HCl) produces the desired amidine acid F. 
The starting materials used in the various schemes depicted above are either commercially available or may be prepared according to known methods in the art.